Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-β-mediated activation of the ALK5-Smad 3 pathway

Young A. Yoo, Myoung Hee Kang, Jun Suk Kim, Sang Cheul Oh

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)

Abstract

It is known that the activation of hedgehog (Hh) signaling is involved in the progression and invasion of various tumors, including gastric carcinoma. In this study, we investigated the impact of transforming growth factor (TGF)-β signaling on the sonic hedgehog (Shh)-mediated invasion of gastric cancer cells. We found that higher concentrations of N-Shh enhanced cell motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells that were treated with KAAD-cyclopamine (a Shh signaling inhibitor) or anti-Shh blocking antibodies. In addition, the N-Shh-induced migration and invasiveness of gastric cancer cells were reduced by treatment with anti-TGF-β blocking antibody or TGF-β1 small interfering RNA (siRNA) in presence of N-Shh when compared with control groups. Furthermore, TGF-β1 secretion, TGF-β-mediated transcriptional response, expression of activin receptor-like kinase (ALK) 5 protein and phosphorylation of Smad 3 were also enhanced by treatment with N-Shh, but not KAAD-cyclopamine, anti-Shh or TGF-β1 blocking antibodies. Blockade of the ALK5 kinase in the presence of N-Shh significantly inhibited phosphorylation of Smad 3, activity of matrix metalloproteinases and Shh-induced cell motility/invasiveness. Importantly, transient expression of ALK5 siRNA or Smad 3 siRNA reduced the ability of N-Shh to stimulate migration and invasion of those cells compared with the cells treated with non-specific control siRNA. In summary, these results indicate that Shh promotes motility and invasiveness of gastric cancer cells through TGF-β-mediated activation of the ALK5-Smad 3 pathway. Additionally, our findings are the first to suggest a role and mechanism for Shh signaling as it relates to the metastatic potential of gastric cancer, thereby indicating potential therapeutic molecular targets to decrease metastasis.

Original languageEnglish
Pages (from-to)480-490
Number of pages11
JournalCarcinogenesis
Volume29
Issue number3
DOIs
Publication statusPublished - 2008 Mar

ASJC Scopus subject areas

  • Cancer Research

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